Field of the Invention
The invention relates to antagonists of IL-17 isoforms and their uses in diagnosis and therapy, especially for the treatment or prevention of cancers or autoimmune and chronic inflammatory diseases.
Background
The interleukin 17 (IL-17) family comprises 6 interleukins (IL-17A, IL-17B, IL-17C, IL-17D, IL-17E=IL-25 and IL-17F) and their receptors (IL-17RA, IL-17RB, IL-17RC, IL-17RD and IL-17RE) (Gaffen, S. L. (2009) “Structure and signalling in the IL-17 receptor family” Nature reviews. Immunology 9(8): 556-567). IL-17A exists as a homodimer (IL-17A/A) or heterodimer (IL-17A/F) (Gaffen, S. L. (2009) “Structure and signalling in the IL-17 receptor family” Nature reviews. Immunology 9(8): 556-567).
IL-17A and IL-17F bind a trimeric complex of IL-17RA and IL-17RC whose expressions are ubiquitous. IL-17A and IL-17F are mainly produced by Th17 cells, a subset of T lymphocytes. The biological role of IL-17A and IL-17F is to participate to host defense against microbial or fungal infections by inducing an acute inflammatory response leading to release of pro-inflammatory cytokines, chemokines, antimicrobial peptides and matrix metalloproteinases from fibroblasts, keratinocytes, endothelial and epithelial cells (Iwakura, Y., H. Ishigame, et al. (2011) “Functional specialization of interleukin-17 family members” Immunity 34(2): 149-162). IL-17A also recruits neutrophils to the inflammatory sites (Iwakura, Y., H. Ishigame, et al. (2011) “Functional specialization of interleukin-17 family members” Immunity 34(2): 149-162). However, chronic or ectopic production of IL-17A and IL-17F is involved in the development of autoimmune and chronic inflammatory diseases as evidenced in mouse models of Experimental Autoimmune Encephalomyelitis, Collagen-Induced Arthritis (CIA) or SKG arthritic mice, in various models of colitis and psoriasis (Iwakura, Y., H. Ishigame, et al. (2011) “Functional specialization of interleukin-17 family members” Immunity 34(2): 149-162). In humans, IL-17A and/or IL-17F are for instance involved in Rheumatoid Arthritis (RA), Multiple Sclerosis, Systemic Lupus Erythematosus inflammatory bowel diseases, Crohn's diseases and psioriasis (Iwakura, Y., H. Ishigame, et al. (2011) “Functional specialization of interleukin-17 family members” Immunity 34(2): 149-162). IL-17A triggers a positive feedback loop on IL-6 signaling, including activation of the NFκB and Stat3 in fibroblasts, leading to chronic inflammation. IL-17A and IL-17F are also involved in allergic diseases (Iwakura, Y., H. Ishigame, et al. (2011) “Functional specialization of interleukin-17 family members” Immunity 34(2): 149-162).
The 4 other members of the family were identified recently based on sequence homology, but have been poorly studied so far. IL-17B binds IL-17RB; IL-17C binds IL-17RE, IL-17E binds a complex of IL-17RA and IL-17RB; the receptor of IL-17D is unknown (Gaffen, S. L. (2009) “Structure and signalling in the IL-17 receptor family” Nature reviews. Immunology 9(8): 556-567). IL-17B, IL-17C, IL-17D and IL-17E activate pathways and cytokines release similar to those induced by IL-17A and IL-17F such as NFκb, TNFα, IL-6, IL-8, IL-1β (Lee, J., W. H. Ho, et al. (2001) “IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1” J Biol Chem 276(2): 1660-1664; Starnes, T., H. E. Broxmeyer, et al. (2002) “Cutting edge: IL-17D, a novel member of the IL-17 family, stimulates cytokine production and inhibits hemopoiesis” J Immunol 169(2): 642-646; Stamp, L. K., A. Easson, et al. (2008) “Different T cell subsets in the nodule and synovial membrane: absence of interleukin-17A in rheumatoid nodules” Arthritis Rheum 58(6): 1601-1608; Iwakura, Y., H. Ishigame, et al. (2011) “Functional specialization of interleukin-17 family members” Immunity 34(2): 149-162; Ramirez-Carrozzi, V., A. Sambandam, et al. (2011) “IL-17C regulates the innate immune function of epithelial cells in an autocrine manner” Nat Immunol 12(12): 1159-1166). As IL-17A and IL-17F, IL-17C is important for the defense against bacterial infections (Ramirez-Carrozzi, V., A. Sambandam, et al. (2011) “IL-17C regulates the innate immune function of epithelial cells in an autocrine manner” Nat Immunol 12(12): 1159-1166). As IL-17A and IL-17F, IL-17B and IL-17C also play a role in CIA in mice (Yamaguchi (2007) “IL-17B and IL-17C are associated with TNF-α production and contribute to the exacerbation of inflammatory arthritis” J. Immunol 179: 7128-7136) and expression of IL-17A, IL-17B, IL-17D, IL-17E have been detected in human RA nodules (Stamp, L. K., A. Easson, et al. (2008) “Different T cell subsets in the nodule and synovial membrane: absence of interleukin-17A in rheumatoid nodules” Arthritis Rheum 58(6): 1601-1608). IL-17E, originally named IL-25, is the most divergent member of the family. It has some common (NFκB, IL-6, IL-8) and unique (IL-4, IL-5, and IL-13) targets (Wong, C. K., P. F. Cheung, et al. (2005) “Interleukin-25-induced chemokines and interleukin-6 release from eosinophils is mediated by p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and nuclear factor-kappaB” American journal of respiratory cell and molecular biology 33(2): 186-194; Iwakura, Y., H. Ishigame, et al. (2011) “Functional specialization of interleukin-17 family members” Immunity 34(2): 149-162). IL-17E is involved in asthma by inducing Th2 cell cytokines (Iwakura, Y., H. Ishigame, et al. (2011) “Functional specialization of interleukin-17 family members” Immunity 34(2): 149-162).
In conclusion, it seems that all isoforms exhibit some redundancy of biological functions and targets (although they are produced by different cell types) and may have similar capacity to induce inflammatory mediators such as IL-6 or TNFα and activate oncogenic pathways such as NFκB and Stat3.
Increased IL-17A or IL-17A producing cells (e.g, Th17 cells) have been reported in numerous solid and hematological cancers and may thus be therapeutic target in cancers (Iwakura, Y., H. Ishigame, et al. (2011) “Functional specialization of interleukin-17 family members” Immunity 34(2): 149-162). In contrast, the expression and role of IL-17B, IL-17C, IL-17D, IL-17E and IL-17F have not been evaluated in cancers.